The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 −) advanced/metastatic breast cancer Journal Article
| Authors: | Bardia, A.; Mayer, I.; Winer, E.; Linden, H. M.; Ma, C. X.; Parker, B. A.; Bellet, M.; Arteaga, C. L.; Cheeti, S.; Gates, M.; Chang, C. W.; Fredrickson, J.; Spoerke, J. M.; Moore, H. M.; Giltnane, J.; Friedman, L. S.; Chow Maneval, E.; Chan, I.; Jhaveri, K. |
| Article Title: | The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 −) advanced/metastatic breast cancer |
| Abstract: | Purpose: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. Methods: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 −) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. Results: Patients (N = 152) received GDC-0810 100–800 mg once daily (QD) or 300–400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). Conclusion: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835. © 2022, The Author(s). |
| Keywords: | adult; controlled study; human tissue; treatment outcome; treatment response; aged; gene mutation; human cell; major clinical study; genetics; clinical feature; constipation; drug tolerability; fatigue; advanced cancer; area under the curve; diarrhea; drug efficacy; drug safety; drug withdrawal; side effect; treatment duration; antineoplastic agent; progression free survival; phase 2 clinical trial; anemia; nausea; vomiting; antineoplastic combined chemotherapy protocols; epidermal growth factor receptor 2; cohort analysis; antineoplastic activity; drug potency; pathology; breast neoplasms; abdominal pain; arthralgia; aspartate aminotransferase blood level; coughing; drug dose escalation; oncogene; aspartate aminotransferase; drug accumulation; breast tumor; ligand; ligands; receptor, erbb-2; receptors, estrogen; time to maximum plasma concentration; phase 1 clinical trial; gonadorelin agonist; drug half life; estrogen receptor; dyspepsia; flatulence; postmenopause; metastatic breast cancer; antiestrogen; drug exposure; phase 1; postmenopausal; decreased appetite; proof of concept; estrogen antagonists; humans; human; female; article; palbociclib; hormone receptor positive breast cancer; esr1 gene; selective estrogen receptor degrader; chloroplast dna; hormone receptor negative breast cancer; gdc-0810; hr +; her2 −; brilanestrant; 3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1h-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid |
| Journal Title: | Breast Cancer Research and Treatment |
| Volume: | 197 |
| Issue: | 2 |
| ISSN: | 0167-6806 |
| Publisher: | Springer |
| Date Published: | 2023-01-01 |
| Start Page: | 319 |
| End Page: | 331 |
| Language: | English |
| DOI: | 10.1007/s10549-022-06797-9 |
| PUBMED: | 36401732 |
| PROVIDER: | scopus |
| PMCID: | PMC9823088 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Export Date: 1 February 2023 -- Source: Scopus |
